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J. Biol. Chem., Vol. 276, Issue 37, 34579-34585, September 14, 2001
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From the The accumulation of various
25-hydroxylated C27-bile alcohols in blood and their
excretion in urine are characteristic features of cerebrotendinous
xanthomatosis (CTX) a recessively inherited inborn error of bile acid
synthesis caused by mutations in the mitochondrial sterol
27-hydroxylase (CYP27) gene. These bile alcohols may be
intermediates in the alternative cholic acid side chain cleavage
pathway. The present study was undertaken to identify enzymes and
reactions responsible for the formation of these bile alcohols and to
explain why Cyp27
Side Chain Hydroxylations in Bile Acid Biosynthesis Catalyzed by
CYP3A Are Markedly Up-regulated in Cyp27
/
Mice but Not in Cerebrotendinous Xanthomatosis*
,
,,,, and Department of Gastroenterology, University
of Tsukuba, Tsukuba-city 305-8575, Japan, the
§ Gastrointestinal Division, Department of Medicine, and
Liver Center, the University of Medicine and Dentistry of New
Jersey-New Jersey Medical School, Newark, New Jersey 07103, the
¶ Veterans Affairs Medical Center, East Orange, New Jersey 07018, the ** Department of Medicine, Center for Research,
Prevention, and Treatment of Atherosclerosis, Hadassah University
Hospital, 91120 Jerusalem, Israel, and the
Department of Medicine, University of
California and Veterans Affairs Medical Center,
San Francisco, California 94121
/ mice do not show
CTX-related abnormalities. Microsomal activities of
5
-cholestane-3
,7,12-triol 25- and 26-hydroxylases,
5-cholestane-3,7,12,25-tetrol 23R-,
24S-, and 27-hydroxylases and testosterone
6-hydroxylase, a marker enzyme for CYP3A, in
Cyp27/ mice livers were markedly
up-regulated (5.5-, 3.5-, 6.5-, 7.5-, 2.9-, and 5.4-fold,
respectively). In contrast, these enzyme activities were not increased
in CTX. The activities of 5-cholestane-3,7,12-triol 25- and
26-hydroxylases and 5-cholestane-3,7,12,25-tetrol 23R-, 24R-, 24S-, and
27-hydroxylases were strongly correlated with the activities of
testosterone 6-hydroxylase in control human liver microsomes
from eight unrelated donors. Troleandomycin, a specific inhibitor of
CYP3A, markedly suppressed these microsomal side chain hydroxylations
in both mouse and human livers in a dose-dependent manner.
In addition, experiments using recombinant overexpressed human CYP3A4
confirmed that these microsomal side chain hydroxylations were
catalyzed by a single enzyme, CYP3A4. The results demonstrate that
microsomal 25- and 26-hydroxylations of
5-cholestane-3,7,12-triol and microsomal 23R-, 24R-, 24S-, and 27-hydroxylations of
5-cholestane-3,7,12,25-tetrol are mainly catalyzed by
CYP3A in both mice and humans. Unlike
Cyp27/ mice, CYP3A activity was not
up-regulated despite marked accumulation of
5-cholestane-3,7,12-triol in CTX.
*
This work was supported in part by grants from the
Department of Veterans Affairs Research Service, National Institutes of Health Grants HD-31932 and DK-26756, and Ministry of Education, Science
and Culture of Japan Grant (B)10470130.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: GI Laboratory
(15A), Veterans Affairs Medical Center, 385 Tremont Ave., East Orange, NJ 07018-1095. Tel.: 973-676-1000 (ext. 2288); Fax: 973-676-2991; E-mail: Salenge@UMDNJ.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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